C–N bond formation and cyclization: A straightforward and metal-free synthesis of N-1-alkyl-2-unsubstituted benzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2019.03.028

A straightforward and metal-free synthesis of N-1-alkyl-2-unsubstituted benzimidazoles from the corresponding o-fluoro aryl formamidines and primary amines using microwave irradiation is described. The displacement of -F by the primary amine and cyclizati

Full text of DOI:10.1016/j.tetlet.2019.03.028

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CAN bond formation and cyclization: A straightforward and metal-free
synthesis of N-1-alkyl-2-unsubstituted benzimidazoles
⇑
⇑
Xuejing Liu , Han Cao, Fusheng Bie, Peng Yan, Ying Han
Zaozhuang University and Lunan Institute of Coal Chemical-engineering Technology Research, Zaozhuang 277160, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward and metal-free synthesis of N-1-alkyl-2-unsubstituted benzimidazoles from the corre-
sponding o-fluoro aryl formamidines and primary amines using microwave irradiation is described. The
displacement of -F by the primary amine and cyclization to form the corresponding benzimidazoles took
place in one pot.
Received 10 January 2019
Revised 10 March 2019
Accepted 11 March 2019
Available online xxxx
Ó 2019 Published by Elsevier Ltd.
Keywords:
Benzimidazoles
Formamidine
Cyclization
Microwave
The benzimidazole ring is one of the most important nitrogen-
containing heterocycles, which are widely explored and utilized by
the pharmaceutical industry for drug discovery (FDA approved
drugs containing the benzimidazole motif were found to be the
fifth most commonly used five-membered aromatic nitrogen hete-
rocycle) [1]. Many efforts have been devoted to the development of
methods for the preparation of N-1-alkyl-2-unsubstituted benzim-
idazoles. Among these methods, three representative approaches
have been highlighted for the synthesis of such benzimidazole
derivatives (Scheme 1). The condensation of 1,2-diaminoarene 1
Herein, we report a novel and straightforward method for the
preparation of N-1-alkyl-2-unsubstituted benzimidazoles from o-
fluoro aryl formamidines and the corresponding primary amines
using microwave irradiation.
Firstly, we prepared four substrates (10a–d, Scheme 3) in high
yields (68–95%) via the reaction of compounds 9a–d with DMF in
the presence of benzene sulfonyl chloride at room temperature
for 1 h.
Secondly, formamidine 10a and benzylamine were chosen as
model substrates for reaction optimization. Initial experiments uti-
lizing 10a and 11a (1:1) in THF or 1,4-dioxane in the presence of
DIPEA (or without DIPEA) resulted in the formation of by-product
13 to a significant extent (12a:13 = 1:2 by LC-MS analysis), pre-
sumably due to nucleophilic attack of the dimethylamine which
was formed during desired product formation (Scheme 4).
To overcome this issue, we increased both the reaction temper-
ature and the reaction time. Unfortunately, these attempts failed to
prevent the formation of compound 13. Gratifyingly, increasing the
equivalents of 11a resulted in the decreased formation of by-pro-
duct 13 (Table 1). The base (DIPEA) was not necessary to change
the product:by-product ratio due to the excess of 11a. Compound
11a (5 eq.) in the presence of DIPEA (0.4 mmol) or without DIPEA
gave same ratios of 12a and 13 (Entry 5).
(
Route 1) with formic acid to form benzimidazole 2, followed by
the direct N-alkylation of one nitrogen of the benzimidazole ring
generates two regioisomers 3 and 4. However, the regioselective
alkylation of one nitrogen over the other is difficult in most cases,
giving rise to mixtures of the two regioisomers [2–11]. The alkyla-
tion of 2-nitroaniline 5 (Route 2), nitro group reduction to the
amino group, and then cyclization of 7 with formic acid selectively
gives the desired compound 3 [12–15]. o-Fluoro nitrobenzene
compound 8 can also be used to form intermediate 6 via S Ar sub-
N
stitution by a primary amine (Route 3) [16–20].
After reviewing current methodologies for the synthesis of N-1-
alkyl-2-unsubitituted benzimidazoles, we believed that it might be
N
possible to form the benzimidazole ring via the intramolecular S -
Ar reaction of a formamidine onto a pendant aryl fluoride in one-
pot (Scheme 2).
With the reaction conditions now optimized, we then explored
the scope by employing a diverse set of amines in conjunction with
either 10a–b (Table 2). The general procedure of preparation of
title compound and typical examples were showed [21–24]. The
results showed that both aliphatic amines and benzylamines give
good to moderate yields. Also, free hydroxyl groups and tertiary
⇑
Corresponding authors.
E-mail addresses: liuxuejing@uzz.edu.cn (X. Liu), yhan910@yahoo.com (Y. Han).
https://doi.org/10.1016/j.tetlet.2019.03.028
040-4039/Ó 2019 Published by Elsevier Ltd.
0
Please cite this article as: X. Liu, H. Cao, F. Bie et al., CAN bond formation and cyclization: A straightforward and metal-free synthesis of N-1-alkyl-2-unsub-
stituted benzimidazoles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.03.028

2
X. Liu et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 2
Synthesis of N-1-alkyl-2-unsubstituted benzimidazoles via microwave irradiation.a
Scheme 1. Selected routes for the synthesis of 2-unsubstituted benzimidazoles 3.
Scheme 2. The formation of benzimidazole.
Scheme 3. Synthesis of formamidines 10a–d.
b
Isolated yield.
a
Reagents and conditions: formamidine 10 (0.4 mmol) primary amine 11
(
2.8 mmol), dry DMSO (1 mL), 160–170 °C, 15 min. in a Biotage Initiator.
showed the desired product, single substitution of one and two flu-
orides by benzylamine, and 10c. The reaction of 10c with aniline
and pyrimidin-2-amine, respectively, gave 15% and 7% conversion
of 10c to the desired products at 170 °C for 1 h (LC-MS analysis).
The reactions of 10d with benzylamine and 3-morpholino-
propan-1-amine, respectively, gave 32% and 38% conversion to
the corresponding products at 170 °C for 1 h while 10d remained.
Note that formamidines which contained a strong electron with-
Scheme 4. Formation of compounds 12a and 13.
Table 1
Optimization of the reaction conditions: effect of increasing the equivalents of 11a.a
Conversion of 10ab
Ratio (%) of 12a and 13b
Entry
11a (eq.)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
61
72
77
88
87
94
37:63
52:48
63:37
79:21
80:20c
93:7
2
drawing group (ANO ) and strongly nucleophilic amines are
important to carry out those reactions (see Scheme 5.).
These findings support a mechanism in which fluorine is dis-
placed by benzylamine, followed by rapid cyclization of the amine
onto the pendant formamidine and liberation of dimethylamine
(Scheme 6). The dimethylamine competes with benzylamine as
the nucleophile, giving rise to by-product 13. Predictably, this
by-product formation can be minimized by using a large excess
of benzyl amine giving only the desired product.
100
100
98:2
100:0
a
Reagents and conditions: DMSO (0.5 mL), 10a (0.2 mmol), 160–170 °C, 15 min.
in a Biotage Initiator.
b
Based on LC-MS analysis.
With DIPEA (0.4 mmol) or without DIPEA.
c
amines were tolerated, having no effect on the yields. However, the
reaction of anilines with 10a only resulted in the formation of trace
amounts of the corresponding products (detected by LC-MS
analysis) due to the weak reactivity of anilines. During the reaction
of 10c and 11a, a mixture was detected by LC-MS analysis which
Scheme 5. Synthesis of N-1-alkyl-2-unsubstituted benzimidazoles.
Please cite this article as: X. Liu, H. Cao, F. Bie et al., CAN bond formation and cyclization: A straightforward and metal-free synthesis of N-1-alkyl-2-unsub-
stituted benzimidazoles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.03.028

X. Liu et al. / Tetrahedron Letters xxx (xxxx) xxx
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50 mL flask equipped with a magnetic stirrer bar was added DMF (60 mL)
and benzene sulfonyl chloride (27.2 g, 154 mmol). The solution was stirred for
20 min and the solution turned to slight yellow color. 2-Fluoro-5-
nitroaniline (12 g, 77 mmol) was added as a solid and the mixture stirred for
0 min at room temperature. The solid was filtered and washed with diethyl
[
(
2
Acknowledgments
a
3
We are grateful to the fund supported by Zaozhuang University
and Lunan Institute of Coal Chemical-engineering Technology
Research.
ether and dried under vacuum. The crude material was transferred into a flask
and neutralized by adding NaOH (4 M) and ethyl acetate (150 mL). The
solution was transferred into a funnel, separated, and the organic layers
extracted with ethyl acetate (2 x 100 mL). After combining the organic layers,
it was washed with brine and dried with Na
obtained, 15.5 g, 95% yield. 1H NMR (500 MHz, DMSO-d
.07 (s, 3 H), 7.35 (t, J = 9.77 Hz, 1 H), 7.79 (dt, J=8.77, 3.40 Hz, 1 H), 7.90 (dd,
2
SO
4
for 3 h. A yellow solid was
Appendix A. Supplementary data
6
) dppm 2.97 (s, 3 H),
3
13
J = 7.63, 2.75 Hz, 1 H), 7.98 (s, 1 H); C NMR (126 MHz, DMSO-d
6
) d ppm
C-F = 11.34 Hz)), 144.20, 155.73, 159.21
10FN : 211.0757, found 211.0750.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.03.028.
3
3
3.92, 116.15, 117.21, 141.24 (d, J
1
( JCF = 254.52 Hz); HRMS calcd. for C
9
H
3 2
O
[
22] General procedure for the preparation of N-alkyl-2-unsubstituted
benzimidazoles: To a solution of formamidine 10 (0.4 mmol) in dry DMSO
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[
[
2
Please cite this article as: X. Liu, H. Cao, F. Bie et al., CAN bond formation and cyclization: A straightforward and metal-free synthesis of N-1-alkyl-2-unsub-
stituted benzimidazoles, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.03.028